Methods for Synthesizing Zinc-Lysine-Chloride Complex

ABSTRACT

Disclosed herein are improved methods for the synthesis of zinc-amino acid-halide complexes via reaction of zinc halide and amino acid free base in a solvent comprising a polyol, as well as oral care compositions comprising said complexes made according to said method.

BACKGROUND

Oral cavity bacteria are the primary cause of dental ailments, includingcaries, gingivitis, periodontitis, and halitosis. Oral bacteria formbiofilms which are tightly adhered to the oral surfaces, especially thetooth enamel. With time, these biofilms calcify and turn into tartar,making them more difficult to remove from the tooth surface. Currentat-home dental treatments, such as tooth brushing and mouth rinsing, canprovide only limited benefit in preventing the growth of oral biofilm,or preventing the conversion of biofilm to plaque and tartar. The onlyeffective way to remove plaque and tartar once it has formed is throughcostly, sometimes uncomfortable professional dental treatments such asroot planning and scaling. It would be extremely beneficial to developmeans of preventing the initial formation of oral bacterial biofilms andinhibiting the growth of oral cavity bacteria. Zinc salts such as zincoxide, zinc citrate, and zinc gluconate, have been used in the art fortheir antibacterial effects, but they can sometimes present difficultiesin formulating oral care compositions, or they can sometimes result inundesirable taste or mouthfeel.

Complexes between metal ions and amino acids are known. Some of these,especially complexes between divalent metal ions and basic amino acids,have seen use in the field of oral care for their ability to treatdentinal hypersensitivity. Certain complexes, such aszinc-bis(lysine)-halide and zinc-bis(arginine)-halide, have beendiscovered to form stable, homogenous aqueous solutions, which undercertain conditions, can precipitate zinc hydroxide, zinc oxide and otherzinc species. The formation of such species as zinc oxide and zinchydroxide provides a means of delivering bioactive zinc to the tissuesof the oral cavity. In addition, the precipitation of these salts hasenabled oral care compositions comprising these complexes to effectivelyplug the dentinal tubules of the teeth that transmit sensations ofhypersensitivity.

These stable, soluble zinc-amino acid-halide complexes have also beendisclosed as effective oral anti-bacterial agents. When placed in oralcare formulations, these complexes provide an effective concentration ofzinc ions to the enamel, thereby protecting against erosion, reducingbacterial colonization and biofilm development, and providing enhancedshine to the teeth. These formulations have the added benefit that theydo not exhibit the poor taste and mouthfeel, poor fluoride delivery, andpoor foaming and cleaning associated with conventional zinc-based oralcare products using soluble zinc salts.

Of particular interest are compositions comprising the zinc-aminoacid-halide complex zinc-lysine-chloride complex, designated ZLC, whichmay be formed, for example, by reaction of zinc chloride and lysine freebase in water. ZLC has the chemical structure [Zn(C₆H₁₄N₂O₂)₂Cl]⁺Cl⁻,and may exist in solution of the cationic cation ([Zn(C₆H₁₄N₂O₂)₂Cl]⁺)and the chloride anion, or may be a solid salt, e.g., a crystal,optionally in dihydrate form. Zinc lysine complex may also exist in ahalide free complex, for example, [Zn(C₆H₁₄N₂O₂)₂]²⁺. Zinc amino acidhalide complexes, including zinc-lysine-chloride complexes, have beendisclosed, e.g., in US 2015-0328118A1, US 2015-0335554A1, US2015-0328110A1, and US 2015-0335553A1, the contents of each of which arehereby incorporated by reference in their entireties.

Complexes comprising zinc and amino acid and optionally an anion and/oroxygen, forms a soluble cationic moiety, which in turn may form a saltwith a halide or other anion. When placed in formulation, this complexprovides an effective concentration of zinc ions to the enamel, therebyprotecting against erosion, reducing bacterial colonization and biofilmdevelopment, and providing enhanced shine to the teeth. Moreover, uponuse, the formulation provides a precipitate that can plug the dentinaltubules, thereby reducing the sensitivity of the teeth. While providingefficient delivery of zinc in comparison to formulations with insolublezinc salts, the formulations comprising the zinc-amino acid complex donot exhibit the poor taste and mouthfeel, poor fluoride delivery, andpoor foaming and cleaning associated with conventional zinc-based oralcare products using soluble zinc salts. While oral care compositionscomprising zinc-amino acid-halide complexes such as the ZLC complex areknown, it has been challenging to develop efficient and reliable methodsof manufacturing the ZLC complex.

While the prior art discloses the use of various means of synthesizingzinc-lysine-halide complexes, such as the ZLC complex, there is still aneed for additional methods which provide improved ease, efficiencyand/or yield.

SUMMARY

It has now been discovered that zinc-amino acid-halide complexes, suchas the ZLC complex ([Zn(C₆H₁₄N₂O₂)₂Cl]⁺Cl⁻) can form in improved yieldby reacting a zinc halide, e.g., zinc chloride, with an amino acid freebase in a solvent comprising a polyol (e.g., glycerol). In someembodiments, the solvent is substantially anhydrous. In someembodiments, the molar ratio of zinc halide to amino acid free base isabout 1:1 to about 1:3, or about 1:2.

The invention further provides oral care compositions, for examplemouthwash, oral gel or dentifrice compositions, that comprise thezinc-amino acid-halide complex made according to the present syntheticmethods.

The invention further provides methods of using the compositions of theinvention to reduce and inhibit acid erosion of the enamel, clean theteeth, reduce bacterially-generated biofilm and plaque, reducegingivitis, inhibit tooth decay and formation of cavities, and reducedentinal hypersensitivity, comprising applying a composition of theinvention to the teeth.

Further areas of applicability of the present invention will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating the preferred embodiment of the invention, are intended forpurposes of illustration only and are not intended to limit the scope ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows overlaid ¹³C NMR spectra comparing the ZLC product madeaccording to the present disclosure by reacting zinc chloride and lysinefree base in glycerol (“A”), in comparison to pure ZLC obtained aftercrystallization from ethanol (“B”), ZLC obtained by spray-drying from anaqueous reaction mixture (“C”) and reference lysine HCl standard (“D”).

FIG. 2 shows overlaid FTIR spectra comparing the ZLC product madeaccording to the present disclosure by reacting zinc chloride and lysinefree base in glycerol (“A”), in comparison to pure ZLC obtained aftercrystallization from ethanol (“B”), ZLC obtained by spray-drying from anaqueous reaction mixture (“C”) and reference lysine-HCl standard (“D”).

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses.

The invention therefore provides, in a first embodiment, method ofmaking a zinc-amino acid-halide complex (Method 1), comprising the stepof reacting a zinc halide, e.g., zinc chloride, with an amino acid infree base form in a solvent comprising a polyol. In further embodimentsof Method 1, the present disclosure provides:

-   -   1.1. Method 1 wherein the amino acid is selected from lysine,        glycine and arginine, in free base form.    -   1.2. Method 1 or 1.1 wherein the amino acid is lysine or        arginine.    -   1.3. Method 1.2, wherein the amino acid is lysine.    -   1.4. Any of methods 1.1 to 1.3, wherein the zinc halide is zinc        chloride (ZnCl₂).    -   1.5. Method 1, or any of 1.1 to 1.4, wherein the zinc-amino        acid-halide complex has the formula Zn(AA)₂(Hal)₂ or        Zn(AA)₃(Hal)₂, wherein “AA” is the amino acid and “Hal” is the        halide.    -   1.6. Method 1.5, wherein the amino acid (“AA”) is lysine,        glycine or arginine.    -   1.7. Method 1.5 or 1.6, wherein the halide (“Hal”) is chloride.    -   1.8. Method 1, or any of 1.1 to 1.4, wherein the zinc-amino        acid-halide complex has the formula Zn(Lys)₂Cl₂.    -   1.9. Method 1.8, wherein the zinc-amino acid-halide complex has        the structural formula [Zn(C₆H₁₄N₂O₂)₂Cl]⁺Cl⁻, optionally in the        form of a mono-hydrate or dihydrate (e.g.,        [Zn(C₆H₁₄N₂O₂)₂Cl]⁺Cl⁻—H₂O).    -   1.10. Method 1.9, wherein the zinc-amino acid-halide complex has        a structure wherein the Zn cation is coordinated by two lysine        ligands with two nitrogen atoms from alpha NH₂ groups of the two        lysine ligands and two oxygen atoms from carboxylic groups of        the two lysine ligands in an equatorial plane, having a        distorted square-pyramidal geometry with the apical position        occupied by a chlorine atom, to form a positive cation moiety,        with which a chloride anion is combined to form an ionic salt.    -   1.11. Method 1, or any of 1.1-1.10, wherein solvent comprises        water, e.g., from 0-50% water w/w.    -   1.12. Method 1.11, wherein the solvent comprises from 1-30%        water w/w, e.g., from 5-30% or from 10-30% w/w.    -   1.13. Method 1 or any of 1.1-1.10, wherein the solvent is        substantially anhydrous, e.g., the solvent contains less than or        equal to 1% water w/v.    -   1.14. Method 1.13, wherein the solvent comprises less than 0.5%        water w/v, or less than 0.1% water w/v, or less than 0.05% water        w/v.    -   1.15. Method 1 or any of 1.1-1.14, wherein the polyol is        selected from one or more of a diol, a trial or a tetraol.    -   1.16. Method 1.15, wherein the polyol is selected from one or        more of ethylene glycol, 1,2-propylene glycol, 1,3-propylene        glycol, cyclopentane-1,2-diol, cyclohexane-1,2-diol, neopentyl        glycol, glycerol, 1,2-butanediol, 1,3-butanediol,        1,4-butanediol, 1,5-pentanediol, and pentaerythritol.    -   1.17. Method 1.16, wherein the polyol is selected from one or        more of ethylene glycol, 1,2-propylene glycol, 1,3-propylene        glycol and glycerol.    -   1.18. Method 1.17, wherein the polyol is glycerol.    -   1.19. Method 1, or any of 1.1-1.18, wherein the solvent further        comprises an alcohol, e.g., methanol, ethanol, propanol,        isopropanol, or butanol.    -   1.20. Method 1, or any of 1.1-1.19, wherein the solvent consists        essentially of glycerol (e.g., the solvent is at least 98% w/w        glycerol, or at least 99% w/w glycerol, or at least 99.5% w/w        glycerol).    -   1.21. Method 1, or any of 1.1-1.19, wherein the reaction step of        reacting zinc halide with amino acid free base occurs by        combining only zinc halide (e.g., zinc chloride), amino acid        free base and glycerol in a suitable reaction vessel.    -   1.22. Method 1, or any of 1.1 to 1.21, wherein the reaction step        takes place at 30° C. to 200° C., e.g., at 50° C. to 180° C., or        at 70° C. to 150° C., or at 100° C. to 150° C., or at 50° C. to        100° C., or at 50° C. to 75° C., or at about 60° C. or at about        120° C.    -   1.23. Method 1, or any of 1.1 to 1.22, wherein the method        further comprises the step of removing the solvent, e.g., by        distillation, vacuum distillation, evaporation, freeze-drying,        or spray drying.    -   1.24. Method 1, or any of 1.1 to 1.23, wherein the method        further comprises the step of isolating the zinc-amino        acid-halide complex, e.g., in solid form and/or in substantially        pure form.    -   1.25. Method 1.24, wherein the isolation step is by        precipitation or crystallization.    -   1.26. Method 1.25, wherein the precipitation or crystallization        step comprises the step of adding a suitable solvent to the zinc        halide/amino acid free base/solvent reaction mixture to        precipitate or crystallize out the zinc-amino acid-halide        complex (e.g., wherein the suitable solvent is one in which the        zinc-amino acid-halide complex is poorly soluble or not        soluble).    -   1.27. Method 1, or any of 1.1 to 1.22, wherein the method does        not comprise further purification or isolation of the zinc-amino        acid-halide complex, e.g., the complex is further used as the        solution of the zinc-amino acid-halide complex in the solvent        comprising a polyol.    -   1.28. Method 1, or any of 1.1 to 1.27, wherein the reaction is        substantially complete (e.g., greater than 90% conversion) after        less than 24 hours.    -   1.29. Method 1.28, wherein the reaction is substantially        complete (e.g., greater than 90% conversion) after less than 12        hours or less than 6 hours or less than 4 hours or less than 3        hours, or less than 1 hour, e.g., 1 to 12 hours or 0.5 to 4        hours, or 0.1 to 1 hour.    -   1.30. Method 1 or any of 1.1 to 1.29, wherein the zinc halide        (e.g., zinc chloride) and the amino acid free base are combined        at a molar ratio of 3:1 to 1:3, e.g., 1:1 to 1:2.5 or 1:1.5 to        1:2.5, or about 1:2.    -   1.31. Method 1 or any of 1.1 to 1.30, wherein the reaction        mixture does not comprise an acid, e.g., does not comprise an        aqueous acid.    -   1.32. Method 1 or any of 1.1 to 1.31, wherein the reaction        mixture has a pH of from 6 to 10, e.g., from 6.5 to 10, or 6.5        to 9, or 6.5 to 8, or 7 to 10, or 7 to 9, or 7 to 8.    -   1.33. Method 1 or any of 1.1 to 1.32, wherein the reaction        mixture does not comprise tetrabasic zinc halide (e.g.,        tetrabasic zinc chloride).    -   1.34. A zinc-amino acid-halide complex made according to Method        1 or any of Methods 1.1 to 1.33.

According to the present invention, it has been unexpectedly found thatthe rate of the reaction between zinc halide and amino acid free base,and the yield of the reaction, can be significantly improved by using apolyol solvent, for example glycerol or a glycerol-water mixture.

The invention further provides a composition (Composition 1), e.g., anoral care composition or personal care composition, comprising azinc-amino acid-halide complex made according to Method 1 or any ofmethods 1.1 to 1.34. In further embodiments the invention provides:

-   -   1.1. Composition 1, wherein the composition is an oral care        composition.    -   1.2. Composition 1.1, in the form of a toothpaste, gel,        mouthwash, powder, cream, strip, or gum.    -   1.3. Composition 1 or any of 1.1-1.2, comprising an orally        acceptable base, e.g., a mouthwash, gel, or dentifrice base.    -   1.4. Composition 1 or any of 1.1-1.2, wherein the composition        comprises the zinc-amino acid-halide complex in an amount of        0.05 to 20% by weight of the composition, e.g., from 0.1 to 10%,        or from 0.5 to 5% or from 1 to 3%.    -   1.5. Any of the foregoing compositions in the form of a        dentifrice, wherein the dentifrice base comprises an abrasive,        e.g., an effective amount of a silica abrasive, e.g., 10-30%,        e.g., about 20%.    -   1.6. Any of the foregoing compositions further comprising an        effective amount of a fluoride ion source, e.g., providing 50 to        3000 ppm fluoride.    -   1.7. Any of the foregoing compositions further comprising an        effective amount of fluoride, e.g., wherein the fluoride is a        salt selected from stannous fluoride, sodium fluoride, potassium        fluoride, sodium monofluorophosphate, sodium fluorosilicate,        ammonium fluorosilicate, amine fluoride (e.g.,        N′-octadecyltrimethylendiamine-N,N,N′-tris(2-ethanol)-dihydrofluoride),        ammonium fluoride, titanium fluoride, hexafluorosulfate, and        combinations thereof.    -   1.8. Any of the preceding compositions comprising an effective        amount of one or more alkali phosphate salts, e.g., sodium,        potassium or calcium salts, e.g., selected from alkali dibasic        phosphate and alkali pyrophosphate salts, e.g., alkali phosphate        salts selected from sodium phosphate dibasic, potassium        phosphate dibasic, dicalcium phosphate dihydrate, calcium        pyrophosphate, tetrasodium pyrophosphate, tetrapotassium        pyrophosphate, sodium tripolyphosphate, and mixtures of any of        two or more of these, e.g., in an amount of 1-20%, e.g., 2-8%,        e.g., ca. 5%, by weight of the composition.    -   1.9. Any of the foregoing compositions comprising buffering        agents, e.g., sodium phosphate buffer (e.g., sodium phosphate        monobasic and disodium phosphate).    -   1.10. Any of the foregoing compositions comprising a humectant,        e.g., selected from glycerin, sorbitol, propylene glycol,        polyethylene glycol, xylitol, and mixtures thereof, e.g.        comprising at least 20%, e.g., 20-40%, e.g., 25-35% glycerin.    -   1.11. Any of the preceding compositions comprising one or more        surfactants, e.g., selected from anionic, cationic,        zwitterionic, and nonionic surfactants, and mixtures thereof,        e.g., comprising an anionic surfactant, e.g., a surfactant        selected from sodium lauryl sulfate, sodium ether lauryl        sulfate, and mixtures thereof, e.g. in an amount of from about        0.3% to about 4.5% by weight, e.g. 1-2% sodium lauryl sulfate        (SLS); and/or a zwitterionic surfactant, for example a betaine        surfactant, for example cocamidopropylbetaine, e.g. in an amount        of from about 0.1% to about 4.5% by weight, e.g. 0.5-2%        cocamidopropylbetaine.    -   1.12. Any of the preceding compositions further comprising a        viscosity modifying amount of one or more of polysaccharide        gums, for example xanthan gum or carrageenan, silica thickener,        and combinations thereof.    -   1.13. Any of the preceding compositions further comprising        flavoring, fragrance and/or coloring.    -   1.14. Any of the foregoing compositions comprising an effective        amount of one or more antibacterial agents, for example        comprising an antibacterial agent selected from halogenated        diphenyl ether (e.g. triclosan), herbal extracts and essential        oils (e.g., rosemary extract, tea extract, magnolia extract,        thymol, menthol, eucalyptol, geraniol, carvacrol, citral,        hinokitol, catechol, methyl salicylate, epigallocatechin        gallate, epigallocatechin, gallic acid, miswak extract,        sea-buckthorn extract), bisguanide antiseptics (e.g.,        chlorhexidine, alexidine or octenidine), quaternary ammonium        compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium        chloride, tetradecylpyridinium chloride (TPC),        N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic        antiseptics, hexetidine, octenidine, sanguinarine, povidone        iodine, delmopinol, salifluor, metal ions (e.g., zinc salts, for        example, zinc citrate, stannous salts, copper salts, iron        salts), sanguinarine, propolis and oxygenating agents (e.g.,        hydrogen peroxide, buffered sodium peroxyborate or        peroxycarbonate), phthalic acid and its salts, monoperthalic        acid and its salts and esters, ascorbyl stearate, oleoyl        sarcosine, alkyl sulfate, dioctyl sulfosuccinate,        salicylanilide, domiphen bromide, delmopinol, octapinol and        other piperidino derivatives, nicin preparations, chlorite        salts; and mixtures of any of the foregoing; e.g., comprising        triclosan or cetylpyridinium chloride.    -   1.15. Any of the preceding compositions further comprising a        whitening agent, e.g., a selected from the group consisting of        peroxides, metal chlorites, perborates, percarbonates,        peroxyacids, hypochlorites, and combinations thereof.    -   1.16. Any of the preceding compositions further comprising        hydrogen peroxide or a hydrogen peroxide source, e.g., urea        peroxide or a peroxide salt or complex (e.g., such as        peroxyphosphate, peroxycarbonate, perborate, peroxysilicate, or        persulphate salts; for example calcium peroxyphosphate, sodium        perborate, sodium carbonate peroxide, sodium peroxyphosphate,        and potassium persulfate);    -   1.17. Any of the preceding compositions further comprising an        agent that interferes with or prevents bacterial attachment,        e.g., solbrol or chitosan.    -   1.18. Any of the preceding compositions further comprising a        source of calcium and phosphate selected from (i) calcium-glass        complexes, e.g., calcium sodium phosphosilicates, and (ii)        calcium-protein complexes, e.g., casein phosphopeptide-amorphous        calcium phosphate    -   1.19. Any of the preceding compositions further comprising a        soluble calcium salt, e.g., selected from calcium sulfate,        calcium chloride, calcium nitrate, calcium acetate, calcium        lactate, and combinations thereof.    -   1.20. Any of the preceding compositions further comprising a        physiologically or orally acceptable potassium salt, e.g.,        potassium nitrate or potassium chloride, in an amount effective        to reduce dentinal sensitivity.    -   1.21. Any of the foregoing compositions further comprising an        anionic polymer, e.g., a synthetic anionic polymeric        polycarboxylate, e.g., wherein the anionic polymer is selected        from 1:4 to 4:1 copolymers of maleic anhydride or acid with        another polymerizable ethylenically unsaturated monomer; e.g.,        wherein the anionic polymer is a methyl vinyl ether/maleic        anhydride (PVM/MA) copolymer having an average molecular weight        (M.W.) of about 30,000 to about 1,000,000, e.g. about 300,000 to        about 800,000, e.g., wherein the anionic polymer is about 1-5%,        e.g., about 2%, of the weight of the composition.    -   1.22. Any of the foregoing compositions, wherein the pH of the        composition is approximately neutral, e.g., from pH 6 to pH 8        e.g., about pH 7.    -   1.23. Any of the forgoing compositions for use to reduce and        inhibit acid erosion of the enamel, clean the teeth, reduce        bacterially-generated biofilm and plaque, reduce gingivitis,        inhibit tooth decay and formation of cavities, and reduce        dentinal hypersensitivity.

The present disclosure further provides a method of using Composition 1,et seq., to reduce and inhibit acid erosion of the enamel, clean theteeth, reduce bacterially-generated biofilm and plaque, reducegingivitis, inhibit tooth decay and formation of cavities, and/or reducedentinal hypersensitivity, the method comprising applying an effectiveamount of a composition of the invention, e.g., any of Composition 1, etseq. to the teeth, and optionally then rinsing with water or aqueoussolution sufficient to trigger precipitation of zinc salts from thecomposition.

For example, in various embodiments, the invention provides a method to(i) reduce hypersensitivity of the teeth, (ii) reduce plaqueaccumulation, (iii) reduce or inhibit demineralization and promoteremineralization of the teeth, (iv) inhibit microbial biofilm formationin the oral cavity, (v) reduce or inhibit gingivitis, (vi) promotehealing of sores or cuts in the mouth, (vii) reduce levels of acidproducing bacteria, (viii) increase relative levels of non-cariogenicand/or non-plaque forming bacteria, (ix) reduce or inhibit formation ofdental caries, (x), reduce, repair or inhibit pre-carious lesions of theenamel, e.g., as detected by quantitative light-induced fluorescence(QLF) or electrical caries measurement (ECM), (xi) treat, relieve orreduce dry mouth, (xii) clean the teeth and oral cavity, (xiii) reduceerosion, (xiv) whiten teeth, (xv) reduce tartar build-up, and/or (xvi)promote systemic health, including cardiovascular health, comprisingapplying any of Compositions 1, et seq. as described above to the oralcavity of a person in need thereof, e.g., one or more times per day. Theinvention further provides Compositions 1, et seq. for use in any ofthese compositions.

Without intending to be bound by theory, it is believed that theformation of the zinc amino acid halide proceeds via formation of thezinc halide then coordination of amino acid residues around a centralzinc. For example, using reaction of zinc oxide with lysinehydrochloride in water as an example, the zinc can react with lysineand/or lysine.HCl to form a clear solution of Zn-lysine-chloride complex(ZnLys₃Cl₂), wherein Zn⁺⁺ is located in an octahedral center coordinatedwith two oxygen and two nitrogen atoms in the equatorial plane comingfrom two lysine's carboxylic acids and amine groups respectively. Thezinc is also coordinated to the third lysine via its nitrogen andcarboxylic oxygen, at the apical position of the metal geometry.

In another embodiment, a zinc cation is complexes with two amino acidresidues and two chloride residues. For example, where the amino acid islysine, the complex has the formula [Zn(C₆H₁₄N₂O₂)₂Cl]⁺Cl⁻. In thiscomplex, Zn cation is coordinated by two lysine ligands with two N atomsfrom NH₂ groups and O atoms from carboxylic groups in an equatorialplane. It displays a distorted square-pyramidal geometry with the apicalposition occupied by a Cl⁻ atom. This novel structure gives rise to apositive cation moiety, to which a Cl⁻ anion is combined to form anionic salt.

Other complexes of zinc and amino acid are possible, and the preciseform is dependent in part on the molar ratios of the precursorcompounds, e.g., if there is limited halide, halide-free complexes mayform, e.g. ZnOLys₂, having a pyramid geometry, with the equatorial planethat is same as the above compound (Zn is bound to two oxygen and twonitrogen atoms from different lysines), wherein the top of the pyramidis occupied by an O atom. Thus, in some embodiments, Method 1 et seq.may result in mixtures of different soluble zinc complexes, some withand some without halide as a part of the complex.

Mixtures of complexes and/or additional complex structures, e.g.,involving multiple zinc ions based on the zinc structure, are possibleand contemplated within the scope of the invention. When the complexesare in solid form, they may form crystals, e.g. in hydrated form.

Irrespective of the precise structure of the complex or complexes,however, the interaction of the zinc and the amino acid convertsinsoluble zinc oxide or zinc salts to a highly soluble complex atapproximately neutral pH. With increasing dilution in water, however,the complex disassociates, and the zinc ion converts to insoluble zincoxide. This dynamic is unexpected—typically ionic compositions becomemore soluble at higher dilution, not less—and this facilitatesdeposition of the zinc precipitate on the teeth upon administration, inthe presence of saliva and with rinsing. This precipitation occludes thedentinal tubules, thereby reducing hypersensitivity, and also provideszinc to the enamel, which reduces acid erosion, biofilm and plaqueformation.

It will be understood that other amino acids can be used in place oflysine in the foregoing scheme. It will also be understood that,although the zinc, amino acid and optionally halide may be primarily inthe form of precursor materials or in the form of an ionic complex,there may be some degree of equilibrium, so that the proportion ofmaterial which is actually in complex compared to the proportion inprecursor form may vary depending on the precise conditions offormulation, concentration of materials, pH, presence or absence ofwater, presence or absence of other charged molecules, and so forth.

The rate of precipitation from the formulation can be modulated byadjusting concentration of the complex in the stock solution, andchanging the ratio of the stock to water. A more diluted formula leadsto faster precipitation and is thus preferred when a fast treatment isdesired.

As used herein, the terms “polyol,” “tetraol,” “triol,” and “diol”refers to organic compounds bearing, respectively, at least two hydroxygroups, four hydroxy groups, three hydroxy groups, or two hydroxygroups, wherein said hydroxy groups are bound to aliphatic carbon atoms(i.e., not aromatic carbon atoms). These terms do not embrace compoundshaving any other functional groups. Thus, polyols, tetraols, triols anddiols, as used herein, can be generally described as compounds having aformula C_(n)H_(m)(OH)_(y), wherein y is at least two. These termsinclude cyclic and polycyclic compounds (e.g., cycloalkane polyols), butnot phenols or other aromatic compounds. In some embodiments, polyolsare C2-10 alkane polyols and/or C2-10 cycloalkane polyols.

As used herein, the term “alcohol” excludes polyols. As such, “alcohol”refers to organic compounds bearing a single aliphatic hydroxy groupwithout any other functional groups. In some embodiments, alcohol refersto compounds having a formula C_(n)H_(m)(OH)_(y), wherein y is 1. Thisterm includes cyclic and polycyclic compounds (e.g., cycloalkanols), butnot phenols or other aromatic compounds. In some embodiments, alcoholsare C1-10 alkanols and/or C1-10 cycloalkanols.

As used herein, “zinc halide” refers to the binary compound betweendivalent zinc and halogen, such as zinc fluoride (ZnF₂), zinc chloride(ZnCl₂), zinc bromide (ZnBr₂), or zinc iodide (ZnI₂). Zinc halides mayoptionally be used in their hydrate forms. As such, the term “zinchalide” as used herein also embraces zinc halide hydrates of the formula(ZnX₂)(H₂O)_(n) wherein n can be 1, 1.5, 2.5, 3, or 4. “Zinc halide”does not include tetrabasic zinc halides, such as tetrabasic zincchloride, which has the formula Zn₅(OH)₈Cl₂. Tetrabasic zinc chloride ismore properly known by the name zinc chloride hydroxide, and it commonlyexists as the monohydrate.

The benefits of the oral care compositions of the invention arenumerous. By providing zinc ions and zinc containing compounds that canrelease zinc ions in oral cavities, the oral care compositions of theinvention provide antimicrobial, antiplaque, antigingivitis,anti-malodor, anticaries, and anticalculus benefits. The occludingparticles and the surface deposits are compounds containing zinc(particularly ZnO), as well as other zinc derivatives which can releasezinc ions into oral cavities and provide the various benefits asrecognized above. Additional benefits include but are not limited toanti-attachment, anti-periodontitis and anti-bone loss, as well aspromotion of wound healing.

A second benefit is the anti-erosive properties of zinc ions, which formanti-erosive deposits on tooth surfaces through oxidation andhydrolysis. The surface deposits, as well as the occluding particles,can react with and neutralize acids, thus protecting the dental surfacefrom the erosive effects of the acids. In this regard, the more surfacedepositions/occlusion the treatments lead to, the more efficacious thetreatments are, and therefore zinc-arginine and zinc-lysine arepreferred. It is also noted that when the surface deposits and occludingparticles neutralize acids, beneficial zinc ions and amino acids (infra)can be released, providing oral care benefits other than anti-erosion.

A third benefit is anti-sensitivity benefit as a result of theocclusion. Occlusion of dentin tubules leads to sensitivity relief.

A fourth benefit is the benefit associated with amino acids. Theoccluding particles and surface deposits contain the corresponding aminoacids, such as arginine and lysine. These amino acids provide multiplebenefits. For example, basic amino acids lead to higher pH of the plaqueand can provide anticaries benefits.

Examples of amino acids include, but are not limited to, the commonnatural amino acids, e.g.: lysine, arginine, histidine, glycine, serine,threonine, asparagine, glutamine, cysteine, selenocysteine, proline,alanine, valine, isoleucine, leucine, methionine, phenylalanine,tyrosine, tryptophan, aspartic acid, and glutamic acid. In someembodiments the amino acid is a neutral or acidic amino acid, e.g.,glycine.

In certain embodiments, compositions according to the present disclosuremay be anhydrous. By anhydrous, there is less than 5% by weight water,optionally less than 4, less than 3, less than 2, less than 1, less than0.5, less than 0.1 down to 0% by weight water. Especially in suchcompositions, the zinc-amino acid-halide complex may be added to thecomposition as a solution in glycerol, e.g., a concentrated solution inglycerol.

Unless stated otherwise, all percentages of composition components givenin this specification are by weight based on a total composition orformulation weight of 100%.

The compositions and formulations as provided herein are described andclaimed with reference to their ingredients, as is usual in the art. Aswould be evident to one skilled in the art, the ingredients may in someinstances react with one another, so that the true composition of thefinal formulation may not correspond exactly to the ingredients listed.Thus, it should be understood that the invention extends to the productof the combination of the listed ingredients.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight. The amounts given are based on the active weightof the material.

EXAMPLES

The general reaction for formation of ZLC is as follows:

ZnCl₂+2Lysine→[Zn(Lysine)₂Cl]Cl(ZLC)+2H₂O

An approximately 1:2 molar ratio of zinc chloride to lysine free basemay be suspended or dissolved in a suitable solvent and stirred untilthe reactants disappear, indicating completion of the formation of thesoluble ZLC complex.

Prior art methods of preparing ZLC complex by combining zinc oxide andlysine hydrochloride in aqueous solution typically required very longreaction times (e.g., 12 hours or more, 24 hours or more, or up to 3days) for completion of the reaction. For example, WO 2015/195118discloses a synthesis method comprising reacting a 1:2 molar ratio ofzinc oxide and lysine hydrochloride in water followed by stirring atroom temperature for 12 hours. WO 2015/195117 discloses a methodcomprising reacting a 1:2 molar ratio of zinc oxide and lysinehydrochloride in dilute aqueous hydrochloric acid (at a pH of 5-6)followed by stirring at room temperature for several hours. In addition,other prior art methods also teach the reaction of zinc chloride andlysine free base in water to form ZLC complex. Such prior art methodsshare the additional drawback, however, that the removal of water from areaction mixture is considerably more difficult than the removal of anorganic solvent. Water has a relatively high boiling point, combinedwith a very high heat of vaporization, making the removal of water bythermal means very energy intensive. Furthermore, it has become commonto formulate oral care compositions in the form of anhydrouscompositions making it necessary to provide ZLC complex in an anhydrousform.

The present invention overcomes these difficulties by providing ZLCcomplex in a solvent or solvent mixture much more amenable to solventremoval or direct incorporation into oral care compositions.

Example 1: ZLC Synthesis in Anhydrous Glycerol

Synthesis:

17.6 g of L-lysine free base (0.12 mol) is added to 400 g of glycerol(>99.5%), followed by the addition of 8.2 g of zinc chloride (0.06 mol).The mixture is stirred at 800 rpm speed at room temperature overnight.All solids dissolve to yield a clear, colorless solution. Based on theraw materials combined for the reaction mixture, the expected ZLCconcentration in glycerol is 6% (w/w). After stirring overnight, analiquot of the reaction mixture (“Sample A”) is analyzed using NMR andFTIR in comparison to pure ZLC crystal dissolved in glycerol. Inaddition, an aliquot of the reaction mixture (“Sample A”) is dilutedwith methanol and analyzed using liquid chromatography electrosprayionization-tandem mass spectrometry (LC-MS) methods.

Comparative Syntheses:

A second preparation of ZLC complex is made by combining zinc oxide andlysine hydrochloride in distilled water (without added acid). Thereaction mixture is stirred for 3 days at room temperature, at whichtime all of the suspended solids had dissolved. A sample of thisreaction mixture is spray dried to afford a white amorphous solid. Asample (“Sample C”) of this solid is dissolved in glycerol for NMR andFTIR analysis.

A sample of the white amorphous solid is then crystallized from ethanolto afford a white crystalline solid. A sample (“Sample B”) of this solidis dissolved in glycerol for NMR and FTIR analysis.

LCMS Analysis:

LC-MS analysis is performed using an AB Sciex tandem mass spectrometer(AB Sciex LLC, Framingham, Mass., USA) equipped with an ESI interfaceand Agilent 1260 capillary LC system (Model Agilent 1260, AgilentTechnologies, Palo Alto, Calif., USA) with a DAD detector (G1315C) andan Agilent Zorbax SB-Aq column with 2.1 mm i.d.×50 mm dimension and 3.5μm particle size (Agilent Technologies, Palo Alto, Calif., USA Part No.871700-914). The mobile phase is methanol at a flow rate was 70 μL/min(injection volume 1 μL). The AB Sciex tandem mass spectrometer isoperated in the positive-ion mode with nitrogen as curtain gas at 10psi, ion source gas at 10 psi. ESI IonSpray voltage is set at 5.5 kV inESI interface. The declustering and entrance potential are set at 80 Vand 5.5 V, respectively. The temperature of the ionization interface ismaintained at 550° C. For total ion count (TIC) mode, the MS screenrange is from 50 to 1000 m/z.

NMR Analysis:

¹³C NMR studies are performed on a Bruker Avance spectrometer(Bruker-Biospin, Billerica, Mass., USA) with a 5 mm BBI probe operatingat 500.0 MHz for ¹H and 125.7 MHz for ¹³C in glycerol at 25° C. All ¹³CNMR spectra are obtained using an ¹H decoupling sequence (“zgig” fromBruker pulse-program library) with a repetition time of 15 sec and 8192transients. An aliquot of the reaction mixture is directly transferredinto a 5 mm NMR tube and the ¹³C NMR spectrum is recorded.

FTIR Analysis:

Infrared spectra are collected using a Bruker Vertex 70 FTIRspectrometer equipped with a GladiATR diamond ATR accessory (Piketechnologies, Madison, Wis.). The spectral range is 80-4000 cm⁻¹ and aresolution of 4 cm⁻¹ is used. All measurements are carried out at roomtemperature on as-prepared glycerol solutions without any additionalsample preparation.

LCMS Results:

The LCMS spectrum shows a single major LC peak demonstrating the typicalzinc isotopic triplet cluster at 354.3, 356.3 and 358.3 m/z. Thismatches the MS spectrum previously obtained for the ZLC complex, the m/z354/356/358 triplet corresponding to the Zn(lysine)₂ complex fragment.

NMR Results:

NMR results are shown in FIG. 1. The ¹³C-NMR spectrum of the dilutedreaction sample is compared to standard spectra of L-lysine HCl inglycerol (“Sample D”) as well as Samples B and C. The chemical shift ofthe carbonyl carbon in the experimental sample is located at 180 ppm asa single peak, which matches the peak in the Sample B and C controls,and which is different than the carbonyl carbon of the Sample D lysinestandard at 173 ppm. This finding demonstrates formation of ZLC complex,and absence of unreacted lysine, in the reaction mixture according tothe present invention. This finding is also consistent with the ZLCcomplex's structure having the lysine carboxyl groups bound to the zincion center.

In addition, while the crystallized ZLC Sample B spectrum also shows anabsence of lysine starting material, the spray dried aqueous reactionmixture of Sample C demonstrates a weak but visible peak for unreactedlysine.

FTIR Results:

FIG. 2 displays a comparison of infrared spectra for Samples A, B, C andD, as described above. FIG. 2(A) shows the full IR spectrum, while FIG.2(B) shows a close-up view of the lysine peaks that are free of overlapfrom the background glycerol spectrum. The spectra demonstrate thepresence of free lysine bands near 1520 cm⁻¹ and 1630 cm⁻¹ in thespray-dried ZLC Sample C, as compared to the pure ZLC crystal Sample B.In contrast, the sample prepared according to the present invention,Sample A, displays a profile that closely resembles the pure ZLC crystal(Sample B) with the exception of an extra band located near 1650 cm⁻¹.This latter band is attributed to the presence of water in this reactionmixture. Subtraction of the water peak, as shown in FIG. 2(C),demonstrates that Sample A's vibrational profile is substantiallyidentical to that of the pure ZLC crystal, suggesting that this newlysynthesized material has a lysine local structure that is similar to ZLCcrystal.

While the invention has been described with respect to specific examplesincluding presently preferred modes of carrying out the invention, thoseskilled in the art will appreciate that there are numerous variationsand permutations of the above described systems and techniques. It is tobe understood that other embodiments may be utilized and structural andfunctional modifications may be made without departing from the scope ofthe present invention. Thus, the scope of the invention should beconstrued broadly as set forth in the appended claims.

1. A method of making a zinc-amino acid-halide complex, comprising thestep of reacting zinc halide with an amino acid free base in a solventcomprising a polyol.
 2. The method of claim 1, wherein the amino acid isselected from lysine, glycine and arginine, in free base form.
 3. Themethod of claim 2, wherein the amino acid is lysine.
 4. The method ofclaim 3, wherein the zinc halide is zinc chloride.
 5. The method ofclaim 1, wherein the zinc-amino acid-halide complex has the formulaZn(AA)₂(Hal)₂ or Zn(AA)₃(Hal)₂, wherein “AA” is the amino acid and “Hal”is the halide.
 6. The method of claim 4, wherein the zinc-aminoacid-halide complex has the formula Zn(Lys)₂Cl₂, optionally, wherein thestructural formula is [Zn(C₆H₁₄N₂O₂)₂Cl]⁺Cl⁻.
 7. The method of claim 1,wherein solvent comprises water.
 8. The method of claim 1, wherein thesolvent is substantially anhydrous.
 9. The method of claim 1, whereinthe polyol is selected from one or more of a diol, a trial or a tetraol.10. The method of claim 1, wherein the polyol is selected from one ormore of ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol,cyclopentane-1,2-diol, cyclohexane-1,2-diol, neopentyl glycol, glycerol,1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol, andpentaerythritol.
 11. The method of claim 1, wherein the solvent furthercomprises an alcohol.
 12. The method of claim 1, wherein the solventconsists essentially of glycerol.
 13. The method of claim 1, wherein themethod further comprises the step of removing the solvent bydistillation, vacuum distillation, evaporation, freeze-drying, or spraydrying.
 14. The method of claim 1, wherein the method further comprisesthe step of isolating the zinc-amino acid-halide complex in solid formand/or in substantially pure form.
 15. The method of claim 14, whereinthe isolation step is by precipitation or crystallization.
 16. Themethod of claim 1, wherein the reaction is substantially complete afterless than 24 hours.
 17. The method of claim 16, wherein the reaction issubstantially complete after less than 6 hours or less than 4 hours orless than 3 hours, or less than 1 hour.
 18. The method of claim 1,wherein the zinc chloride and the amino acid free base are combined at amolar ratio of 3:1 to 1:3.
 19. A zinc-amino acid-halide complex madeaccording to claim
 1. 20. An oral care or personal care compositioncomprising the complex according to claim 19.